A mesoscale finite element modeling approach for understanding brain morphology and material heterogeneity effects in chronic traumatic encephalopathy.

Chronic Traumatic Encephalopathy (CTE) affects a significant portion of athletes in contact sports but is difficult to quantify using clinical examinations and modeling approaches. We use an in silico approach to quantify CTE biomechanics using mesoscale Finite Element (FE) analysis that bridges with macroscale whole head FE analysis. The sulci geometry produces complex stress waves that interact with one another to create increased shear stresses at the sulci depth that are significantly larger than in analyses without sulci (from 0.5 to 18.0 kPa). Sulci peak stress concentration regions coincide with experimentally observed CTE sites documented in the literature. HighlightsSulci introduce stress localizations at their depth in the gray matterSulci stress fields interact to produce stress concentration sites in white matterDifferentiating brain tissue properties did not significantly affect peak stresses.

A Mechanical Brain Damage Framework Used to Model Abnormal Brain Tau Protein Accumulations of National Football League Players.

A mechanics-based brain damage framework is used to model the abnormal accumulation of hyperphosphorylated p-tau associated with chronic traumatic encephalopathy within the brains of deceased National Football League (NFL) players studied at Boston University and to provide a framework for understanding the damage mechanisms. p-tau damage is formulated as the multiplicative decomposition of three independently evolving damage internal state variables (ISVs): nucleation related to number density, growth related to the average area, and coalescence related to the nearest neighbor distance. The ISVs evolve under different rates for three well known mechanical boundary conditions, which in themselves introduce three different rates making a total of nine scenarios, that we postulate are related to brain damage progression: (1) monotonic overloads, (2) cyclic fatigue which corresponds to repetitive impacts, and (3) creep which is correlated to damage accumulation over time. Different NFL player positions are described to capture the different types of damage progression. Skill position players, such as quarterbacks, are expected to exhibit a greater p-tau protein accumulation during low cycle fatigue (higher amplitude impacts with a lesser number), and linemen who exhibit a greater p-tau protein accumulation during high cycle fatigue (lower amplitude impacts with a greater number of impacts). This mechanics-based damage framework presents a foundation for developing a multiscale model for traumatic brain injury that combines mechanics with biology.

The social gradient of fractures at any skeletal site in men and women: data from the Geelong Osteoporosis Study Fracture Grid.

UNLABELLED: Age-specific and age-standardized associations between socioeconomic status (SES) and fractures in adults showed a social gradient of fracture, irrespective of fracture site. Compared to the highest SES, males in the lowest SES group had a sixfold increased odds for any fracture, whilst females had a twofold increased odds. INTRODUCTION: The effective identification of predisposing risk factors for fracture requires understanding any association with SES. These investigations should consider both sexes, span the adult age range and include any fractures. We investigated age- and sex-specific and age-standardized associations between SES and fractures at any skeletal site in Australians aged ≥ 50 years. METHODS: Incident fractures that occurred 2006-2007 for adults aged ≥ 50 years were identified from radiological reports extracted for the Barwon Statistical Division, in south-eastern Australia. SES was determined by cross-referencing residential addresses with Australian Bureau of Statistics census data and then categorized in quintiles. We compared frequencies of observed vs. expected fractures for SES quintiles using χ (2) comparison, calculated age-specific fracture incidence across SES and compared age-standardized fracture rates in SES quintile 1 to quintile 5. RESULTS: We identified 3943 incident fractures (69.4 % female); 47.4 % had occurred at major osteoporotic fracture (MOF) sites (hip, humerus, spine and forearm/wrist). Differences existed in observed vs. expected fractures across SES quintiles (p ≤ 0.001, sexes combined); all fractures showed an inverse association with SES (p ≤ 0.001, sexes combined). Compared to the highest SES quintile, individuals from the lowest SES quintile had between two to six times greater standardized fracture rates. CONCLUSIONS: Disadvantaged men and women have an increased fracture incidence compared to their less disadvantaged counterparts. The large differences in fracture rates between SES groups warrant further research into designing appropriate, targeted interventions for those demographics at most risk.

Is there an interaction between socioeconomic status and FRAX 10-year fracture probability determined with and without bone density measures? Data from the Geelong Osteoporosis Study of female cohort.

FRAX(©) evaluates 10-year fracture probabilities and can be calculated with and without bone mineral density (BMD). Low socioeconomic status (SES) may affect BMD, and is associated with increased fracture risk. Clinical risk factors differ by SES; however, it is unknown whether aninteraction exists between SES and FRAX determined with and without the BMD. From the Geelong Osteoporosis Study, we drew 819 females aged ≥50 years. Clinical data were collected during 1993-1997. SES was determined by cross-referencing residential addresses with Australian Bureau of Statistics census data and categorized in quintiles. BMD was measured by dual energy X-ray absorptiometry at the same time as other clinical data were collected. Ten-year fracture probabilities were calculated using FRAX (Australia). Using multivariable regression analyses, we examined whether interactions existed between SES and 10-year probability for hip and any major osteoporotic fracture (MOF) defined by use of FRAX with and without BMD. We observed a trend for a SES * FRAX(no-BMD) interaction term for 10-year hip fracture probability (p = 0.09); however, not for MOF (p = 0.42). In women without prior fracture (n = 518), we observed a significant SES * FRAX(no-BMD) interaction term for hip fracture (p = 0.03) and MOF (p = 0.04). SES does not appear to have an interaction with 10-year fracture probabilities determined by FRAX with and without BMD in women with previous fracture; however, it does appear to exist for those without previous fracture.

Prior fracture as a risk factor for future fracture in an Australian cohort.

SUMMARY: This study investigated the influence of prior fracture on the risk of subsequent fracture. There was a higher risk of subsequent fracture in both young and older adult age groups when Australian males or females had already sustained a prior fracture. Fracture prevention is important throughout life for both sexes. INTRODUCTION: The purpose of this study was to determine the impact of prior fracture on the risk of subsequent fracture across the adult age range in Australian males and females. METHODS: All-cause fractures were grouped into age categories for males and females enrolled in the Geelong Osteoporosis Study (Australia) using retrospective self-report data and prospective radiology-confirmed data. For all age categories, the relative risk (RR and 95% confidence interval (CI)) of subsequent fracture in a later age category was compared between those with prior fracture and those without. RESULTS: For both sexes, childhood fracture increased the risk of subsequent fracture in adolescence (males: RR 21.7; 95% CI 16.0, 27.4; females: RR 8.1; 3.5, 12.8). Males with adolescent fracture had increased risk of subsequent fracture in early adulthood (RR 11.5; 5.7, 17.3) and mid-adulthood (RR 13.0; 6.3, 19.7). Additionally, males with young adulthood or mid-adulthood fracture had increased risk of subsequent fracture in the following age group (RR 11.2; 4.4, 17.9, and RR 6.2; 0.8, 11.7, respectively). Mid-adult fractures increased the risk of subsequent fracture in older adulthood (RR 6.2; 0.8, 11.7). Females with childhood or adolescent fracture had an increased risk of fracture in young adulthood (RR 4.3; 0.7, 7.9, and RR 10.5; 4.4, 16.6), and prior fracture in older adult life increased the risk of subsequent fracture in old age (RR 14.9; 6.4. 23.3). CONCLUSIONS: Fracture prevention strategies may be more effective if attention is directed towards individuals with prior fracture at any age as they have a higher likelihood of sustaining a subsequent fracture later in life.

Fracture risk among older men: osteopenia and osteoporosis defined using cut-points derived from female versus male reference data.

SUMMARY: We explored the effect of using male and female reference data in a male sample to categorise areal bone mineral density (BMD). Using male reference data, a large proportion of fractures arose from osteopenia, whereas using female reference data shifted the fracture burden into normal BMD. INTRODUCTION: The purpose of this study was to describe fracture risk associated with osteopenia and osteoporosis in older men, defined by areal BMD and using cut-points derived from male and female reference data. METHODS: As part of the Geelong Osteoporosis Study, we followed 619 men aged 60-93 years after BMD assessments (performed 2001-2006) until 2010, fracture, death or emigration. Post-baseline fractures were radiologically confirmed, and proportions of fractures in each BMD category were age-standardised to national profiles. RESULTS: Based on World Health Organization criteria, and using male reference data, 207 men had normal BMD at the femoral neck, 357 were osteopenic and 55 were osteoporotic. Using female reference data, corresponding numbers were 361, 227 and 31. During the study, 130 men died, 15 emigrated and 63 sustained at least one fracture. Using male reference data, most (86.5 %) of the fractures occurred in men without osteoporosis on BMD criteria (18.4 % normal BMD, 68.1 % osteopenia). The pattern differed when female reference data were used; while most fractures arose from men without osteoporosis (88.2 %), the burden shifted from those with osteopenia (34.8 %) to those with normal BMD (53.4 %). CONCLUSIONS: Decreasing BMD categories defined increasing risk of fracture. Although men with osteoporotic BMD were at greatest risk, they made a relatively small contribution to the total burden of fractures. Using male reference data, two-thirds of the fractures arose from men with osteopenia. However, using female reference data, approximately half of the fractures arose from those with normal BMD. Using female reference data to define osteoporosis in men does not appear to be the optimal approach.

Examining the impact of reimbursement on referral to bone density testing for older adults: 8 years of data from the Barwon Statistical Division, Australia.

UNLABELLED: In 2007, Medicare Australia revised rei:mbursement guidelines for dual energy X-ray absorptiometry (DXA) for Australians aged ≥70 years; we examined whether these changes increased DXA referrals in older adults. Proportions of DXA referrals doubled for men and tripled for women from 2003 to 2010; however, rates of utilization remained low. INTRODUCTION: On April 1, 2007 Medicare Australia revised reimbursement guidelines for DXA for Australians aged ≥70 year; changes that were intended to increase the proportion of older adults being tested. We examined whether changes to reimbursement increased DXA referrals in older adults, and whether any sex differences in referrals were observed in the Barwon Statistical Division. METHODS: Proportions of DXA referrals 2003-2010 based on the population at risk ascertained from Australian Census data and annual referral rates and rate ratios stratified by sex, year of DXA, and 5-year age groups. Persons aged ≥70 years referred to the major public health service provider for DXA clinical purposes (n = 6,096; 21 % men). RESULTS: DXA referrals. Proportions of DXA referrals for men doubled from 0.8 % (2003) to 1.8 % (2010) and tripled from 2.0 to 6.3 % for women (all p < 0.001). For 2003-2006, referral ratios of men/women ranged between 1:1.9 and 1:3.0 and for 2007-2010 were 1:2.3 to 1:3.4. Referral ratios <2007:≥2007 were 1:1.7 for men aged 70-79 years (p < 0.001), 1:1.2 for men aged 80-84 years (p = 0.06), and 1:1.3 for men 85+ years (p = 0.16). For women, the ratios <2007:≥2007 were 1:2.1 (70-79 years), 1.1.5 (80-84 years), and 1:1.4 (85+ years) (all p < 0.001). CONCLUSIONS: DXA referral ratios were 1:1.6 (men) and 1:1.8 (women) for 2007-2010 vs. 2003-2006; proportions of referrals doubled for men and tripled for women from 2003 to 2010. Overall, rates of DXA utilization remained low. Policy changes may have had minimal influence on referral; thus, ongoing evaluation over time is warranted.

Social disadvantage, bone mineral density and vertebral wedge deformities in the Tasmanian Older Adult Cohort.

UNLABELLED: The relationship between social disadvantage and bone mineral density (BMD) is complex and remains unclear; furthermore, little is known of the relationship with vertebral deformities. We observed social disadvantage to be associated with BMD for females, independent of body mass index (BMI). A lower prevalence of vertebral deformities was observed for disadvantaged males. INTRODUCTION: The relationship between social disadvantage and BMD appears complex and remains unclear, and little is known about the association between social disadvantage and vertebral wedge deformities. We examined the relationship between social disadvantage, BMD and wedge deformities in older adults from the Tasmanian Older Adult Cohort. METHODS: BMD and wedge deformities were measured by dual-energy X-ray absorptiometry and associations with extreme social disadvantage was examined in 1,074 randomly recruited population-based adults (51 % female). Socioeconomic status was assessed by Socio-economic Indexes for Areas values derived from residential addresses using Australian Bureau of Statistics 2001 census data. Lifestyle variables were collected by self-report. Regression models were adjusted for age, BMI, dietary calcium, serum vitamin D (25(OH)D), smoking, alcohol, physical inactivity, calcium/vitamin D supplements, glucocorticoids and hormone therapy (females only). RESULTS: Compared with other males, socially disadvantaged males were older (65.9 years versus 61.9 years, p = 0.008) and consumed lower dietary calcium and alcohol (both p ≤ 0.03). Socially disadvantaged females had greater BMI (29.9 ± 5.9 versus 27.6 ± 5.3, p = 0.002) and consumed less alcohol (p = 0.003) compared with other females. Socially disadvantaged males had fewer wedge deformities compared with other males (33.3 % versus 45.4 %, p = 0.05). After adjustment, social disadvantage was negatively associated with hip BMD for females (p = 0.02), but not for males (p = 0.70), and showed a trend for fewer wedge deformities for males (p = 0.06) but no association for females (p = 0.85). CONCLUSIONS: Social disadvantage appears to be associated with BMD for females, independent of BMI and other osteoporosis risk factors. A lower prevalence of vertebral deformities was observed for males of extreme social disadvantage. Further research is required to elucidate potential mechanisms for these associations.

Analysis of artificially degraded DNA using STRs and SNPs--results of a collaborative European (EDNAP) exercise.

Recently, there has been much debate about what kinds of genetic markers should be implemented as new core loci that constitute national DNA databases. The choices lie between conventional STRs, ranging in size from 100 to 450 bp; mini-STRs, with amplicon sizes less than 200 bp; and single nucleotide polymorphisms (SNPs). There is general agreement by the European DNA Profiling Group (EDNAP) and the European Network of Forensic Science Institutes (ENFSI) that the reason to implement new markers is to increase the chance of amplifying highly degraded DNA rather than to increase the discriminating power of the current techniques. A collaborative study between nine European and US laboratories was organised under the auspices of EDNAP. Each laboratory was supplied with a SNP multiplex kit (Foren-SNPs) provided by the Forensic Science Service, two mini-STR kits provided by the National Institute of Standards and Technology (NIST) and a set of degraded DNA stains (blood and saliva). Laboratories tested all three multiplex kits, along with their own existing DNA profiling technique, on the same sets of degraded samples. Results were collated and analysed and, in general, mini-STR systems were shown to be the most effective. Accordingly, the EDNAP and ENFSI working groups have recommended that existing STR loci are reengineered to provide smaller amplicons, and the adoption of three new European core loci has been agreed.

Validation of a 21-locus autosomal SNP multiplex for forensic identification purposes.

A single nucleotide polymorphism (SNP) multiplex has been developed to analyse highly degraded and low copy number (LCN) DNA template, i.e. <100 pg, for scenarios including mass disaster identification. The multiplex consists of 20 autosomal non-coding loci plus Amelogenin for sex determination, amplified in a single tube PCR reaction and visualised on the Applied Biosystems 3100 capillary electrophoresis (CE) system. Allele-specific primers tailed with shared universal tag sequences were designed to speed multiplex design and balance the amplification efficiencies of all loci through the use of a single reverse and two differentially labelled allele denoting forward universal primers. As the multiplex is intended for use with samples too degraded for conventional profiling, a computer program was specifically developed to aid interpretation. Critical factors taken into account by the software include empirically determined extremes of heterozygous imbalance (Hb) and the drop-out threshold (Ht) defined as the maximum peak height of a surviving heterozygous allele, where its partner may have dropped out. The discrimination power of the system is estimated at 1 in 4.5 million, using a White Caucasian population database. Comparisons using artificially degraded samples profiled with both the SNP multiplex and AMPFISTR SGM plus (Applied Biosystems) demonstrated a greater likelihood of obtaining a profile using SNPs for certain sample types. Saliva stains degraded for 147 days generated an 81% complete SNP profile whilst short tandem repeats (STRs) were only 18% complete; similarly blood degraded for 243 days produced full SNP profiles but only 9% with STRs. Reproducibility studies showed concordance between SNP profiles for different sample types, such as blood, saliva, semen and hairs, for the same individual, both within and between different DNA extracts.

Mutations of RegIalpha are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia.

BACKGROUND & AIMS: The RegIalpha gene (Reg) encodes a secretory protein proposed to regulate islet beta-cell and gastric mucous cell growth. Reg is expressed in rat gastric enterochromaffin-like (ECL) cells. The aim of this study was to examine Reg expression in human corpus and to determine the identity of Reg in ECL cell carcinoid tumors in hypergastrinemic patients. METHODS: Reg messenger RNA (mRNA) abundance was quantified by Northern blot in extracts of gastric corpus from patients with and without ECL cell tumors and in AR4-2J cells stimulated by gastrin; cellular origins were determined by immunocytochemistry. Mutations of Reg were determined by reverse-transcription polymerase chain reaction, cloning, and sequencing, and the mutated protein was expressed in HIT-T15 cells. RESULTS: Reg mRNA abundance was increased approximately threefold in the corpus of hypergastrinemic patients compared with controls, and was enriched in 3 of 7 ECL cell carcinoid tumors but not in non-endocrine cell gastric polyps. In AR4-2J cells, gastrin stimulated Reg mRNA abundance; this was eliminated by the gastrin/cholecystokinin B antagonist L-740,093 (10(-9) mol/L). Immunocytochemistry indicated that Reg was located in both chief cells and ECL cells in human corpus. Mutations of Reg were identified in 3 of 5 patients with ECL cell carcinoid tumors; in 2 cases, mutation of the initiator methionine residue led to exclusion of the protein from the secretory pathway. CONCLUSIONS: Gastrin regulates Reg mRNA abundance in human corpus. Mutations of Reg that prevent secretion are associated with ECL cell carcinoids, suggesting a function as an autocrine or paracrine tumor suppressor.

Small cardioactive peptide gene: structure, expression and mass spectrometric analysis reveals a complex pattern of co-transmitters in a snail feeding neuron.

The small cardioactive peptides (SCPs) are an important group of neural cotransmitters in molluscs where they are known to play both central and peripheral modulatory roles in the control of feeding behaviour. Here we show that in the snail Lymnaea the SCP gene exists in one interrupted copy that produces a single species of transcript which encodes a prepropeptide containing two structurally related SCPs SGYLAFPRMamide (SCP(A)) and pQNYLAFPRMamide (SCP(B)). In situ hybridization was used to localize expression specifically to the soma of several types of motoneurons in the feeding system of Lymnaea, including the giant B2 foregut motoneurons. The peptide content of individual B2 cell bodies was analysed by matrix-assisted laser desorption/ionization mass spectrometry and the structures of the SCPs predicted from the cloned gene were confirmed in these cells by post-source decay fragmentation analysis. Identical stimulatory activity for the two SCP peptides was demonstrated by their application to the isolated foregut, suggesting that their co-release from the B2 cells may play an important part in the co-modulation of gut motility, together with acetylcholine and the myomodulin family of peptides.

Distance modulation of neural activity in the visual cortex.

Humans use distance information to scale the size of objects. Earlier studies demonstrated changes in neural response as a function of gaze direction and gaze distance in the dorsal visual cortical pathway to parietal cortex. These findings have been interpreted as evidence of the parietal pathway's role in spatial representation. Here, distance-dependent changes in neural response were also found to be common in neurons in the ventral pathway leading to inferotemporal cortex of monkeys. This result implies that the information necessary for object and spatial scaling is common to all visual cortical areas.

Expression of an alternatively spliced ercc1 messenger-RNA species, is related to reduced DNA-repair efficiency in human T-lymphocytes.

We have previously shown that in non-drug-selected human T lymphocytes, DNA repair is the primary determinant of cellular resistance to cisplatin (1). In this system, we have assessed mRNA levels of expression of the nucleotide excision repair (NER) genes ERCC1 and XPA, as well as the alternatively spliced species of ERCC1 which lacks exon VIII. The focus of these studies, was to try to identify the possible relative roles of normal XPA, full-length ERCC1, and alternatively spliced ERCC1, in a system where DNA repair is a clear determinant of cisplatin resistance. ERCC1 expression was directly related to cisplatin-DNA adduct repair capability, as well as directly related to cisplatin resistance, suggesting a primary role for ERCC1 in effecting DNA repair. XPA expression was approximately equivalent in each cell line, regardless of the level of DNA repair activity, suggesting a helper role for the product of this gene. The mRNA levels of the alternatively spliced species of ERCC1 were strongly inversely related to DNA repair activity, suggesting a possible inhibitory influence on the DNA repair process. This interpretation is consistent with alternative splicing of several known oncogenes, where the alternatively spliced species has an inhibitory effect on the full-length gene product. The NER pathway appears to be vitally important in effecting cisplatin resistance in non-drug-selected T lymphocytes. Further, it appears that NER may have at least one inhibitory regulatory component.

Endstopping and curvature.

Hypercomplex or endstopped visual cortical neurons are usually supposed to be concerned with length or end point analysis. However, recent evidence demonstrates that endstopped neurons are curvature-selective, a connection that we explore here in some detail. A model of endstopped simple cells is developed and a variety of computational simulations examine the connection of the model to the reported length and orientation responses of endstopped neurons. Even and odd versions of the model are described, both of which are shown to be curvature-selective. Even-symmetric instances of the model respond well to thin curves over a range of curve orientation and curvature, independent of sign of curvature. In contrast, odd-symmetric instances respond to both thin and thick curves while exhibiting a more complex curvature-sign dependence--responding in a sign-selective fashion to curved lines but not to curved edges. Finally, the response of the endstopped model to curve singularities is explored, and the possible role of nonendstopped and endstopped cells in building curve descriptions is discussed.

Endstopped neurons in the visual cortex as a substrate for calculating curvature.

Neurons in the visual cortex typically respond selectively to the orientation, and velocity and direction of movement, of moving-bar stimuli. These responses are generally thought to provide information about the orientation and position of lines and edges in the visual field. Some cells are also endstopped, that is selective for bars of specific lengths. Hubel and Wiesel first observed that endstopped hypercomplex cells could respond to curved stimuli and suggested they might be involved in detection of curvature, but the exact relationship between endstopping and curvature has never been determined. We present here a mathematical model relating endstopping to curvature in which the difference in response of two simple cells gives rise to endstopping and varies in proportion to curvature. We also provide physiological evidence that endstopped cells in area 17 of the cat visual cortex are selective for curvature, whereas non-endstopped cells are not, and that some are selective for the sign of curvature. The prevailing view of edge and curve determination is that orientations are selected locally by the class of simple cortical cells and then integrated to form global curves. We have developed a computational theory of orientation selection which shows that measurements of orientation obtained by simple cells are not sufficient because there will be strong, incorrect responses from cells whose receptive fields (RFs) span distinct curves (Fig. 1). If estimates of curvature are available, however, these inappropriate responses can be eliminated. Curvature provides the key to structuring the network that underlies our theory and distinguishes it from previous lateral inhibition schemes.

Effect of exposure to lead on maturation of intestinal iron absorption of rats.

The influence of lead on iron absorption was investigated at various stages of development in rat pups exposed to lead first through mothers' milk and later in their solid diet. Hematocrit, hemoglobin, iron absorption, and tissue iron concentration were measured on d 14, 20, 23, 29, 35, 42, and 63 after birth. Both hematocrit and hemoglobin in the lead-exposed group were significantly below control levels at all periods earlier than d 42 and 63, respectively. Absorption of iron ([59Fe]-ferrous citrate in 10(-4)M FeSO4) from intestinal loops measured over 1/2 h remained at preweaning levels (10-12% of total activity added to the loop) for at least 1 wk after weaning in the lead-exposed rats, whereas in control animals iron absorption fell to adult levels (3-4%) at weaning. Spleen weight was significantly elevated in lead-exposed rats compared with control rats at all ages beyond d 14. However, spleen iron content (micrograms of Fe per gram of tissue) was not significantly elevated in the lead-exposed group before d 42. The results indicate that exposure to lead does not reduce iron absorption from the intestinal tract; thus alteration of intestinal iron absorption does not contribute to lead-induced anemia. Indeed, lead-exposed rats demonstrated increased iron uptake.